CN102695514A - S-adenosylmethionine formulations with enhanced bioavailability - Google Patents

Abstract

The invention relates to compositions and methods to enhance the absorption of S- adenosylmethionine (SAMe) and to methods of treating various disorders or diseases using non-parenteral SAMe formulations with enhanced-absorption and improved bioavailability. The enhanced bioavailability formulations may be used to treat a variety of diseases or disorders, such as for example, psychiatric disorders including, generalized anxiety disorder, obsessive compulsive disorder, post traumatic stress disorder, panic disorder, depressive disorders (e.g. major clinical depression) and dysthymia; as well as treating liver disorders, cancer, autoimmune disorders, inflammatory disorders, joint disorders, gastrointestinal disorders and cardiovascular disease.

Description

S-adenosylmethionine formulation with enhanced bioavailability

Related description

The priority of the U.S. Provisional Patent Application serial number 61/229,194 that the application requires to submit on July 28th, 2009, its all by reference mode be incorporated herein.

Technical field

The present invention relates to be used for the compositions and the method for bioavailability of the improvement of S-adenylic acid-L-methionine (" SAM-e " or " SAMe ").More particularly, the present invention relates to be adjusted in the formulation of the absorption of the exogenous SAMe of gastrointestinal tract, and this formulation administered through oral is used or similarly method provide from wherein expecting the SAMe PC of enough physiological effecies.Through using the formulation of the gastrointestinal absorption that can improve SAMe; The present invention is oriented to the method for in the experimenter, treating disease or illness and/or improving experimenter's nutriture, wherein uses one or more absorptions-promotion property technology to reach enhanced gastrointestinal and absorbs.

Background technology

S-adenylic acid-L-methionine (" SAM-e " or " SAMe ") is naturally occurring chemical compound, and it is present in the tissue of whole body.SAMe comprises various metabolic pathways on molecular level, comprise transmethylation, transsulfuration and aminopropylization (aminopropylation) (for example producing the polyamine apoplexy due to endogenous wind, such as spermidine and the spermine from putrescine).

S-adenylic acid-L-methionine (SAMe)

In health, SAMe is synthetic from aminoacid, methionine and ribonucleoside triphosphote, ATP.In a large amount of clinical trials, the SAMe test is used to treat various diseases, comprises arthritis, hepatic disease and depression.

Begin to think that SAMe supplementation (supplementation) is unpractical because SAMe produce, shipment and store in unstability.Finally develop the stable salt (for example three of two-right-toluenesulfonic acid dithionate of the fourth disulfonate of SAMe p-methyl benzenesulfonic acid dithionate (SAMe p-methyl benzenesulfonic acid dithionate), SAMe, SAMe (di-para-toluene sulfonate disulfate salt of SAMe), SAMe--right-the toluenesulfonic acid dithionate (tri-para-toluene sulfonate disulfate salt of SAMe) etc.) of SAMe.The use standard, knownly be used for these salt of technology preparation that non-parenteral uses, include but not limited to tablet, capsule and pill.For example these formulation also can comprise coating, and it can be used as multiple purpose, for example improves taste and is convenient to swallow and be reduced to stimulation.The stable salt of SAMe is described in, and for example U.S. Patent number 3,954,726 and 4,057,686, its all by reference mode be incorporated herein.Conventional SAMe API provides as comprising the molecular entity of ion with some equilibrium ions.For example, SAMe ion and toluene fulfonate and 2 sulfonic acid equilibrium ions are formed commercially available S-adenosylmethionine dithionate-p-toluene fulfonate (being SAMe toluenesulfonic acid dithionate).When relating to the SAMe administration, the numerical value dosage (usually in milligram) of this area acceptance at present is meant the ionic amount of the SAMe that uses." the 400mg SAMe tablet " of the use SAMe toluenesulfonic acid dithionate of for example, mentioning comprises that the other excipient of equilibrium ion and 200-300mg of the SAMe ion of 400mg, other 370mg is to form the final tablet weight of 1.0-1.1 gram.Therefore, for example in this area usually the SAMe of the 1600mg oral dose of report typically can be the tablet of four this 1.0-1.1 gram dosage once taking.Selectively, the SAMe ion of identical 1600mg dosage also can through multiple tablet other combination use realization, for example, 16 100mg that take in the given time or the SAMe ion of eight tablets of 200mg tablets.The conventional peroral dosage form of SAMe prepares with the SAME ion of about 400mg the most usually; Surpass suchly, bigger dosage form becomes and is difficult to swallow, and considers even during for the SAME ion of 400mg, tablet is very big, is the 1.0-1.1 gram.

The popular conventional view in this area thinks that thereby the gastric juice in the stomach can change the structure of SAMe and/or the absorption that function reduces it, and therefore will walk around under one's belt the specific coating (pH-specific coating) of pH-that any SAMe discharges for Orally administered be considered to be necessary.These " intestinal " coatings are well-known and are used routinely by those skilled in the art.Enteric coating provides barrier, and the dosage form of its protection capsule envelope is in order to avoid extremely hang down the pH environment in the stomach.Although be " pH-sensitivity ", these coatings are designed the medicament with capsule envelope in the protection stomach individually.They begin dissolving (they are designed to meet the pH of the environment that follows stomach closely) at about pH more than 5.5 usually, thereby following dosage form is discharged.Reported various trials with the stability of the SAMe that improves enteric coating with send.Rao etc. describe use enteric coating, the lipotropy soft gelatin capsule, and it begins dissolving (United States Patent (USP) 6,759,395) for 5.5 times at pH.They advise the use of lipophilic materials, as the mode of the medicine of protection capsule envelope to isolate SAMe salt.And SAMe discharges their use standard enteric coatings in order to walk around under one's belt.The use of enteric coating is not beat all; In view of prior art is reported: because at first through gastric juice it is degraded, SAMe can not absorb under one's belt.

Except the SAMe at this area report is claiming of passivation at gastric, around the mechanism of absorption of this chemical compound and the view that metabolism is accepted extensively in addition.Based on the clinical experiment in past, SAMe is quoted as proof to highly dissoluble and high osmosis but is had low bioavailability.Use the research of radiolabeled SAMe to show: SAMe is easy to absorb in the GI road; But plasma analysis shows low bioavailability (Stramentinoli, G., (1987) The American Journal of Medicine 83 (S 5A): 35-42).Therefore, those skilled in the art suppose that the low bioavailability of SAMe is because other factor causes, for example " first pass effect " in liver.Too in 20 years, a large amount of groups have attempted through eliminating at pharmacokinetics, the medicine of various SAMe formulations and RE is sought in distributing understanding the SAMe bioavailability, but do not pass through mechanism of absorption.According to this area routine of the most encyclopedic technical staff; Because before getting into blood " significant liver metabolism "; The SAMe bioavailability is restricted to＜5% (Bottiglieri et al., (1988) Alabama Journal of Medical Sciences 25 (3): 296-301 when oral using; Bottiglieri et al., (1997; Exp.Opin.Invest.Drugs 6 (4): 417-426; Kaye et al., (1990) Drugs 40:124-128).Other medicine is eliminated and kidney metabolism research report: owing to the reason of the bioavailability that reduces; The health accumulation of complete SAMe is unlikely, and shows also that on the contrary " metabolism before the active system " is reason (Giulidori and Cortellaro (1984) European Journal of Clinical Pharmacology 27:119-121; Stramentinoli, G., (1986) Biological Methylation and Drug Design.R.T.Borchardt.New Jersey, Humana Press:315-326).Other view is, after non-parenteral was used, the metabolism of SAMe took place rapidly via transmethylation (and littler degree, transsulfuration and aminopropylization) approach.More specifically be that those skilled in the art propose the methyl removal of SAMe and incorporate in the stable aggregation with low conversion rate, for example protein and phospholipid (Bottiglieri (1997) supra; Stramentinoli (1987) supra), and therefore cause the very limited bioavailability of SAMe self.

Active liver metabolism is taking place in a lot of medicines, and typically cause to their bioavailability shown in SAMe more under the upper limit (cap).Also have the preparation of the support SAMe of a large amount of this area report to absorb the clinical data of (ready absorption).Therefore, low SAMe bioavailability mainly is the first pass effect widely owing to liver, and this is the general rule of this area.

Recently the research cultured cells report that absorbs SAMe is found: the monolayer SAMe through the Caco-2 cell is carried deficiently and is absorbed deficiently through the rat hepatocytes of cultivating.(McMillan?et?al.，(2005)J.of?Pharmacy?and?Pharmacology，57：599)。To confirm as what exogenous SAMe bioavailability be low and wherein improve its method in addition, and this still still has demand.

Summary of the invention

This researcher has found that the hypotonicity of SAMe is following chief reason: 1) the SAMe bioavailability is limited in the body; 2) zones of different of SAMe in the GI road has the differing absorption pattern; And, 3) the non-increase significantly of SAMe metaboilic level in Orally administered back.These discoveries are particular importances, overcome liver metabolism because be different from, and the gastrointestinal that has several methods can change and strengthen medicine absorbs.

The present invention recognizes that the SAMe permeability is that to increase the SAMe bioavailability be possible to the factor low and absorbance through use strengthening this chemical compound.

Exemplary of the present invention relates to and is used for enhancing-adenylic acid-L-methionine (" SAMe ") or as its method and composition of absorption of sta-salt of the mode that increases the SAMe bioavailability.Compare with the conventional non-parenteral dosage form of SAMe, use the bioavailability that improvement is provided in the body of method of the present invention.

The present invention relates to the non-parenteral compositions that promotes the SAMe of property technical tie-up with at least a absorption particularly.Absorption-promotions property technology mode effect in a large number that the absorption of the physiologically acceptable dosage of SAMe is increased comprises for example increasing SAMe in the time of staying in GI road (much more therefore make has chances of absorbing); SAMe is delivered to the zone in GI road with enhanced drug absorption; Increase by " absorption enhancer ", that it increases medicine or change cell or bypass transhipment (comprising the medicament that directly influences tight connection opening or infiltration); The SAMe capsule is enclosed in SAMe directly is delivered in the nano-carrier of cell; Or any of these is regulated the combination of the technology that absorbs.Therefore, " absorption-promotion property technology " is or directly or indirectly influences any excipient, device, mechanism, technology, method, treatment parameter etc. of absorption or the picked-up of SAMe.Can be with many these art designs for exploitation or optimize the inherent cationic property under specific pH level of SAMe, for example, some can make that SAMe keeps absorbing more easily its cationic form (for example in the presence of buffer agent or buffer system).Therefore; Unite unconventional factor for compositions of the present invention; Exist (promptly can more effectively being absorbed by the SAMe of coating) that has or do not have coating of diet (dosage and/or food type and/or beverage), administration time table, the method that absorbs as suitable change SAMe for example, this is within the scope of the invention.Under some conditions, the absorption before SAMe uses-promotion property technology to use for optimizing the SAMe picked-up possibly be necessary.

Use through pH-dependency coating can reach show enhanced-absorb position-specific section that is delivered to the GI road of the SAMe of (also becoming " absorbing window "), this pH-dependency coating discharges the SAMe in the specific zone of the pH-in GI road as target.

Therefore, the certain exemplary embodiment relates to the compositions that comprises pH-dependency coating, and wherein the compositions of pH-dependency coating makes and discharges the section-specific zone of the SAMe of physiologically acceptable dosage in gastrointestinal (GI) road.In order to influence the position-specific effect of SAMe picked-up and bioavailability, pH-dependency coating makes being released in along several zones in whole GI road of SAMe.The absorption of SAMe can run through the total length in GI road, comprises stomach.Through defining enhanced-zone of absorbing of SAMe, can use these zones as directed formulation, thereby guarantee that SAMe absorbs and the better control of bioavailability.PH-dependency coating does not use as the enteric coating that simply is applied to avoid degraded under one's belt in the present invention.PH-dependency coating can be sending as target in the GI road.

Therefore, the formulation that the invention still further relates to the SAMe through sending pH-dependency coating increases the method for the bioavailability of SAMe, and it makes and discharges the SAMe of physiologically acceptable dosage position-zone specific or that pH-is specific in the GI road.

" absorption enhancer " (it also refers to comprise " penetration enhancer ", " the permeability promoter " of common name, the medicament of " promoter "), directly act on the concrete aspect in GI road, for example bypass transhipment, and the absorbance that influences many medicines.

The invention further relates to use absorption enhancer with the absorption of SAMe that increases or promote physiologically acceptable dosage as the compositions of the mechanism that increases the SAMe bioavailability.

Some exemplary of the present invention relates to the close-connected active absorption enhancer of direct adjusting.These are commonly referred to as tight connection penetrating agent or closely connect and regulate or the opening agent.Closely connect is the intercellular connection at the intercellular infiltrative cell of control.Therefore, material (for example API) can not pass through iuntercellular, but must absorb through cell, and therefore makes cell to control to allow anything to pass through.Closely connect the many zones that occur in whole health, comprise face, small intestinal, large intestine and colon, and in zones of different, change density/tight type.In the GI road, closely connect the zone that is meant between contiguous endotheliocyte, and the picked-up that acts on the material of regulating digestion.Closely connect by highly control, and be to form one of the inner chamber environment in oral cavity and/or key element of the barrier between GI road and the health remainder.

The invention still further relates to introduce and closely connect regulator to increase or to promote the compositions of absorption of the SAMe of physiologically acceptable dosage.

Be used to use medicinal, medical, for animals or nutritional preparation that reason goes up the SAMe of acceptable dosage and comprise conventional solid or semi-solid tablet, pill, granule and capsule and, the regularly controlled-release technology of release tech directed, osmotic pumps, layering tablet, multiparticle tablet, nano-carrier or their combination such as the pH-sensitive drug.When relating to " medical " preparation, purpose or treatment, they are intended to comprise " dietetic food ".Dietetic food is defined as under doctor's supervision preparation by U.S. food and Drug Administration (U.S.Food and Drug Administration) and is used for through digestive tract consumption or the food used; And the special diet management of using it for disease or disease; Therefore based on the science principle of generally acknowledging, set up unique dietary requirements through medical evaluation.

Some exemplary of the present invention further relates to the non-parenteral compositions that is used for SAMe, wherein SAMe is formulated as to comprise solid or the semi-solid combination that one or more absorb promotion property technology.The present invention further provides the method for treatment, wherein medicinal, medical, the for animals or nutritional preparation of SAMe and one or more is absorbed to promote the property technology synergy to use.Preferably; Said absorption promotes medicinal, medical, the for animals or nutritional preparation of property technology and said SAMe to use jointly; And even more preferably, said absorption promotes the property technology to be contained in medicinal, medical, the for animals or nutritional preparation of said SAMe.

Absorption-promotion property technology need not form the part of the SAMe that uses, and can it be used separately.The specific mechanism of action that depends on them, can or with the forward and backward of SAMe formulation or use simultaneously the absorption of selecting to promote the property technology immediately.Therefore, the invention still further relates to the novel method of in its experimenter of needs treatment disease or illness, wherein said method comprise with one or more absorption-promotion property technical tie-ups use the SAMe of physiology effective dose.

A little exemplary relate to through being used for the non-parenteral delivering compositions of using; Be used for increasing the method for the bioavailability of SAMe the experimenter; Said composition comprises SAMe and at least a absorption promotion property technology, wherein said absorption promotion property technology or the direct or indirect absorption of doing in order to the SAMe that increases physiologically acceptable dosage.

The disease that can treat with SAMe formulation of the present invention and/or illness are selected from but are not limited to: psychology or mental disease (for example psychotic disease/emotion or OP sexual psychology illness; Be example with depression and material dependency illness respectively), nervous system disease/illness (central nervous system disease is an example with the Alzheimer), other sacred disease/illness (for example headache and sleep disorder), with to the relevant disease of said central nervous system's damage, hepatic disease/illness (for example alcoholic liver disease), cancer (for example entity and haematogenous cancer), joint disease/illness (for example arthritis), inflammatory diseases/illness (for example ulcerative colitis), autoimmune disease/illness (systemic lupus erythematosus (sle) and rheumatic arthritis), degenerative disease/illness (for example amyotrophic lateral sclerosis), soft-tissue disease/illness (for example fibromyalgia illness), pain disease/illness, and height-or low-relevant hereditary illness that methylates, gastroenteropathy/illness, cardiovascular disease/illness, all or part of by oxidation or the inductive illness of radical damage.Other embodiment of the present invention relates to the associating of SAMe and one or more active component, and said active component is write out a prescription routinely or is used in disease or the illness that treats and/or prevents various experimenters.

The accompanying drawing summary

Figure 1A is the comprehensive figure of experimenter's in pilot study SAMe mean plasma concentration with respect to the time; Use SAMe formulation a kind of of three kinds of sections of 800mg-specific to the experimenter; This formulation comprises coating, GI road (duodenum/jejunum that design is closing on; Square), GI road (ileum/ascending colon endways; Triangle) discharges SAMe and metering in whole GI road (circle); And

Figure 1B is the view in the amplification of the figure of Figure 1A, and it better gives prominence to the separation between harmonic(-)mean PC curve.

Fig. 2 be show separately and in the presence of EDTA or do not having calcium in the presence of pass the infiltrative figure of SAMe of Caco-2 human colon adenocarcinoma cell's monolayer.Comprising Propranolol controls as high osmosis;

Fig. 3 be separately with at the various tight infiltrative figure that are connected the demonstration SAMe that passes the Caco-2 human colon adenocarcinoma cell in the presence of the regulator.

Fig. 4 is mean plasma concentration and SAMe metabolism, the S-adenosyl homocysteine (SAH) of SAMe from seven commercially available p-methyl benzenesulfonic acid dithionate SAMe experimenters that the use 1600mg dosage figure with respect to the time.

Fig. 5 be from seven respectively use 400mg dosage not by the figure of the mean plasma concentration of SAMe the experimenter of the formulation of the oral SAMe of coating with respect to the time,

Detailed Description Of The Invention

It is opposite with the usual condition of this area that this researcher has been found, and the SAMe permeability is low and finds that also the zones of different of SAMe confirmation in the mankind's GI road has the differing absorption pattern.And they find the influence that the horizontal minimally of metabolite is used by exogenous SAMe in blood of SAMe metabolite, and the bioavailability of the bright low exogenous SAMe in this also clear face of land is not mainly due to the first pass effect in the liver widely.Finally, the known tight connection regulator model monolayer that passes cell increases the permeability of SAMe significantly.The meaning of these discoveries is great, because the gastrointestinal that has the technology of several possible can change and increase SAMe absorbs.

The present invention recognizes because the SAMe infiltration is low, and it is possible increasing the SAMe bioavailability through the factor of using the absorbance that strengthens this chemical compound.

Certain exemplary embodiment of the present invention relates to the absorption of regulating and improve the SAMe that non-parenteral uses and the compositions of bioavailability.Relevant exemplary provides the Drug therapy of using compositions to be used for some disease and/or illness and/or as supplementary and/or as the method for dietetic food.Other embodiment of the present invention relates to the associating of SAMe and one or more active component, and said active component is write out a prescription routinely or is used in disease or the illness that treats and/or prevents various experimenters.

The term " SAMe " that uses like this paper is meant S-adenylic acid-L-methionine and variant thereof, S-adenosylmethionine.As before shown in the structural formula that represents, SAMe appears as charged kind, and its ionizing ionization state is along with pH changes.As described before, in its solid form, SAMe exists with the salt that comprises SAME ion and one or more equilibrium ions.Usually find SAMe for separately or with the sta-salt form (the p-toluenesulfonic acid for example being arranged) of one or more other salifiable materials of shape as negative equilibrium ion; For example, mineral or organic acid and/or aminoacid are (referring to US 3,893; 999, its all by reference mode be incorporated herein).Other stable SAMe salt is described in, and for example, US 5,128,249, the stable especially salt of its open SAMe.The various forms of SAMe are to be applicable to the present invention.Therefore, " SAMe " that use like this paper is meant stable salt and amorphous form and merocrystalline form and the crystal form of SAMe, and is the ionic species of SAMe when existing in vivo.Can use the amorphous form of the SAMe of any particle size and particle size distribution.

Being used for non-parenteral, to use the formulation of SAMe be typically to provide as solid or semi-solid products or dosage form, for example tablet, capsule or pill, and contain " capsule envelope " medicine and one or more protectiveness coated cores " host material " usually." product " or " dosage form " that use like this paper is meant any solid or semi-solid formulation or preparation that non-parenteral is used that be used for.Non-parenteral formulation as described herein or preparation comprise the oral delivery system, are example with tablet, paste, capsule, granule, capsule sheet, lozenge etc.; And delivery system percutaneous, transmucosal or that suck, be example with aerosol, irrigation, topical cream, paste, patch, lozenge etc., all these are well-known and complete evidence in this area.Can use dosage regimen clinical, medicinal or for animals to use these formulations.Non-parenteral SAMe dosage form also can be used as dietetic food or diet or supplementary to be provided.

The SAMe formulation that configurable non-parenteral is used makes the release of the SAMe that can prolong the capsule envelope.The U.S. Patent application of owning together 2009/0088404 provides the novel formulation of the SAMe formulation that prolong to discharge, its by reference mode be incorporated herein.As disclosed among the U.S.2009/0088404; The whole bag of tricks that the compositions of the prolongation release that can be used in the various types of medicines of preparation is arranged; And according to expection, at least a SAMe compositions for preparing the prolongation release that enhanced bioavailability character is arranged that can be used in these methods.The type of the SAMe compositions that the prolongation of containing within the scope of the invention discharges comprises that the infiltrative dosage form with one or more enteric coating coatings, the substrate that prolongs release, pulsed discharge formulation and prolong the formulation that discharges, and all these are described in detail among the U.S.2009/0088404.

" the physiology effective dose " of the SAMe that uses like this paper is intended to be included in the dosage of the SAMe that uses under the dosage regimen of definition, is used for or clinical, medicinal, medical, for animals, diet or nutritional purpose.Therefore; " the physiology effective dose " of SAMe comprises that acceptable dosage, the acceptable dosage of diet and threpsology on the treatment effective dose of SAMe, pharmaceutically acceptable dosage, veterinarily acceptable dosage, the nutraceutical go up acceptable dosage and as the acceptable dosage of dietetic food, it all is included in the use of the present invention.

The relative bioavailability of SAMe formulation is to use well-known technology to measure through its pharmacokinetic profiles figure of assessment, for example TG-AUC (AUC; It is after the administration to the measurement of total exposure of the experimenter of SAMe in blood plasma), C _Max(that is the SAMe maximum concentration of after administration, measuring in blood plasma) and T _Max(that is, in the time when reaching maximum plasma sa Me concentration behind the drug administration)-all these are measured in the art and are described widely.

The present invention relates in some embodiments treat and/or prevent and be selected among the experimenter but be not restricted to the method for following illness: psychology or mental disease (for example psychotic disease/emotion or OP sexual psychology illness; Be example with depression and material dependency illness respectively), nervous system disease/illness (central nervous system disease; With the Alzheimer is example), other sacred disease/illness (for example headache and sleep disorder), with to the relevant disease of said central nervous system's damage, hepatic disease/illness (for example alcoholic liver disease), cancer (for example entity and haematogenous cancer), joint disease/illness (for example arthritis), inflammatory diseases/illness (for example ulcerative colitis), autoimmune disease/illness (systemic lupus erythematosus (sle) and rheumatic arthritis), degenerative disease/illness (for example amyotrophic lateral sclerosis), soft-tissue disease/illness (for example fibromyalgia illness), pain disease/illness, and height-or low-relevant hereditary illness that methylates, gastroenteropathy/illness, cardiovascular disease/illness, all or part of by oxidation or the inductive illness of radical damage; This method comprises exemplary composition of the present invention from the absorption of the SAMe that strengthens the physiology effective dose to said experimenter that use, thereby enhanced-absorption provides the increase of SAMe bioavailability.

Certain exemplary embodiment of the present invention relates to the compositions and the method for usefulness that is used to strengthen the SAMe of physiology effective dose as they of diet in the experimenter or supplementary of using.Can use one or more nutritional properties variablees to measure as the usefulness of diet or supplementary, the concentration of for example improving and, emotion, nutriture and liver situation.

SAMe absorbs and the absorption of bioavailability-promotion property technology as improving

Absorb the restrictive factor of bioavailability of the system be SAMe in case recognize SAMe, investigation increases or the method for regulating its absorption is suitable.Any or directly or indirectly promote SAMe to contain within the scope of the invention in the method for the absorption of whole health; For example comprise; Increase the time of staying of SAMe in the GI road; Thereby making has more picked-up chances, with the target area that SAMe is delivered to the GI road of the drug absorption characteristic with increase, incorporates " absorption enhancer " (comprising " penetration enhancer " and " promoter ") into; Increase medicine or change cell or bypass transhipment (comprise and directly influence close-connected medicament), the SAMe capsule is enclosed in SAMe directly is delivered in the nano-carrier of cell; SAMe is remained its cationic form, regulate diet and/or administration time table, do not send and regulate the associating of " technology " that absorb by the SAMe of coating or with any of these.When relating to " gastrointestinal tract " or " GI road ", it is intended to comprise from mouth/face oral cavity until the whole zone in esophagus, stomach, small intestinal, large intestine and colorectum zone.

Increase the mechanism of the retention time of stomach

Use the for example gastric retentive dosage forms of medicine (GRDF), comprise buoyant, how much, biological viscosity and expansible dosage form,, can reach the retention time of increase SAMe stomach its wriggling and mechanical contraction property that is designed to resist stomach,

GI section-specific directed formulation

The position of SAMe-specific to be delivered to along a plurality of positions in GI road for understanding and regulating that SAMe absorbs be useful because the unique environments of the different sections of whole intestinal can influence the absorption of different pharmaceutical.Especially, show that in the GI road low infiltrative medicine tends to be absorbed in the specific region along this road.Therefore, in order to control absorption, must their site of delivery of control.

Directed site of delivery comprises one or more in mouth, stomach, duodenum, jejunum, ileum, colon and the rectum in the GI road.Along the pH in GI road under one's belt low to 1 to some section intestinal 8 in change.The GI road is the high complexity environment that different pH zone is arranged, and this pH zone changes in the place, and a large amount of factors that comprise diet are depended in its variation.This pH typically is and from stomach, is low to moderate most in the pH zone the highest in little and large intestine.

Large intestine is to comprise the last organ in GI road and comprise colon and rectum.Large intestine is the position that water absorbs and Excreta forms.As dental sector, the blood of discharging rectum at first is not transported to liver.Therefore, the absorption that in rectum, takes place (for example, from rectal suppository and enema) gets into systemic circulatory system and has no biotransformation, otherwise this biotransformation possibly occur in the liver.

Except pH; Other physiologic factor (for example surface area, enzyme with activity transport protein, closely be connected porosity and colon microbiologic population) influences drug absorption; And the method as the bioavailability that influences SAMe is regulated one or more these factors in any zone in GI road, this is within the scope of the invention.

The known Duan Genggao that closes on that transports in the GI road through the bypass of tight connection mediation of those skilled in the art is an example with duodenum, jejunum and ileum.Bypass transhipment section endways is under more, for example colon.

Certain exemplary embodiment of the present invention relates to the new compositions of the SAMe that comprises pH-dependency coating, and wherein the compositions of pH-dependency coating makes and discharges the section-specific zone of the SAMe of physiologically acceptable dosage in gastrointestinal (GI) road.In order to influence SAMe position-specific absorption and bioavailability, can be configured to make the release of SAMe can be pH-dependency coating in several zones in whole GI road.

Certain exemplary embodiment of the present invention relates to the compositions that in (or " not coating ") formulation of non-enteric coating, comprises SAMe.The SAMe blood plasma level opposite with the present usual condition of this area, that this researcher discovery can be released into SAMe in the stomach and cause improving effectively, and therefore, enteric coating is not to be used to reach the key of absorption.

Absorption enhancer

The epithelium of human body and barrier endothelium are delivered to systemic circulatory system and major obstacle are provided to the organ that unique environments is arranged (for example central nervous system) for medicine.In these barriers, there are several transporting pathway, can its potential exploitation be used to promote drug permeability and absorption.Compare (via the transcytosis of transport protein, adsorbate and receptor-mediation) with changeing cellular pathways, the parietal cell flow of cell and molecule is very limited.In 40 years, many groups absorb or permeability promoter in exploitation in the past.These " promoter " produce as revising iuntercellular connection and the infiltrative method of parietal cell.

Therefore, certain exemplary embodiment of the present invention relates to the compositions of the SAMe that comprises physiologically acceptable dosage that unites with one or more " absorption enhancers "." absorption enhancer " (for example parietal cell permeability promoter (PPE) or " promoter ") typically falls into the wide chemical species of cleaning agent or surfactant, non-surface-active agent (for example unsaturated ring urea), fatty acid, bile acid and chelating agen.Each medicament can improve the absorption of the active component of oral delivery through one or more mechanism, this mechanism with the mucous rheology covered on changing, make cell membrane lipid twolayer fluidization, influence close-connected complex, inhibitory enzyme or transport protein is active, influence medicine self and other is an example with some modes.The absorption enhancer that uses among this paper can come functionating through the interaction which comprises a large amount of chemistry or physics: the SAMe dissolubility is regulated in (1); (2) improve the mucous diffusibility of SAMe; (3) from enzyme pH, inner chamber and/or brush border, protect SAMe; (4) from unspecific binding site, protect SAMe; And the permeability of SAMe through port and/or gastrointestinal epithelial cell is improved in (5).

The example of the absorption enhancer that is suitable for using in the present invention includes but not limited to: routine is called CPE (chemosmosis promoter; For example listed in the following table 1) micromolecule promoter; Bile salts; Surfactant; Phospholipid; Glyceride and fatty acid; And peptide hormone; Cytoskeleton perturbation agent (cytoskeletal perturbing agents); Oxide; Calcium ion (Ca ⁺⁺) chelating agen and ionophore.

The tabulation of table 1.CPE

The AS anion surfactant; The CS cationic surfactant; The ZS zwitterionic surfactant; The NS non-ionic surface active agent; The BS bile salts; The FA fatty acid; The FE fatty ester; The FM fatty amine; The sodium salt of SS fatty acid; The ring that NR is nitrogenous; OT other

At present the drug absorption progress of research cause finding closely with the increase of the quantity of conformity membrane, adapter, regulator and signal protein during adhesion is connected.Closely connecting is that the intercellular iuntercellular that forms intercellular barrier connects, and therefore, material (for example micromolecule, protein and medicine) can not pass through iuntercellular, but must absorb through cell, and therefore makes and can control permission by cell what passes through.Closely connect the many zones that occur in whole health, comprise face, small intestinal, large intestine and colon, and in zones of different, change density/tight type.In the GI road, closely connect the zone that is meant between contiguous endotheliocyte, and the picked-up that acts on the material of regulating digestion.Closely connect by highly control, and be to form one of the inner chamber environment in oral cavity and/or key element of the barrier between GI road and the health remainder

Closely connect and have three major functions: (1) constrains in cell together; (2) be limited in proteic the moving of top and the conformity membrane between lower surface of cell; Make the special function (this protection is changeed cell traffic as target) and (3) retardance on each surface of protection (for example in the endocytosis of the receptor-mediation of top surface with in the exocytosis of lower surface) pass through spatial molecule of iuntercellular and ion channel; Therefore, in order in fact to get into (through diffusion or active transport) in the cell through organization material.This approach provides what material is allowed through control.

New tight connection regulator or opening agent are just under development at present, its can be directly closely or adhere to and connect albumen, signal pathway and regulate linkage function or the tight connection relevant as target with the Lipid Rafts micro structure.Directly act on close-connected regulator and comprise the polypeptide class, come from Zonula occludens toxin, bacillus perfringens enterotoxin, the polypeptide that is selected from the phage display that is bonded to the conformity membrane tight junction protein, lipid regulating agent.They can increase bypass transhipment and medicine with reversing sends, and has the potential that is used as drug excipient, sends through the barrier of epithelium and the medicine of blood brain barrier thereby improve medicine.Exemplary " closely connect regulate " that be suitable for using in the present invention includes but not limited to: chitosan, gather (acrylic acid), CD, caprate, spermine, taurocholic acid (comprising sodium salt and other salt form) and other bile acid and/or their salt (cholic acid, sodium cholate or cholic acid potassium) and more medicaments of identifying recently, it comprises the peptide class that derives from Zonula occludens toxin or bacillus perfringens enterotoxin.Therefore, the classification of the tight connection regulator that comprises among this paper comprises: saturated and/or undersaturated fatty acid or their corresponding carboxylic acid salt (for example C6-C24 fat or its carboxylate, particularly C8-C22 fatty acid or its carboxylate; C10-C20 fatty acid or its carboxylate; C6-, C1-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17-, C18-, C19-, C20-, C21-, C22-fatty acid or its carboxylate); Saturated and undersaturated sulfonic acid and sulfonate thereof (for example C6-C24 sulfonic acid or sulfonate, particularly C8-C22 sulfonic acid or sulfonate; C10-C20 sulfonic acid or sulfonate; C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17-, C18-, C19-, C20-, C21-, C22-sulfonic acid or sulfonate); Zwitterionic surfactant (for example 3-(N, N-dimethyl cetyl) propyl sulfonic acid ammonium, decyl dimethyl propyl ichthyodin, myristyl dimethyl propyl ichthyodin, cocamidopropyl propyl amide hydroxyl sulfo betaine (ChemBetaine

CAS), oil-based betaine (ChemBetaine

Oleyl) or chlorination Petiolus Trachycarpi carnitine); Fatty amine (for example C6-C24 fatty amine, particularly C8-C22 fatty amine, C10-C20 fatty amine, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17-, C18-, C19-, C20-, C21-, C22-fatty amine); And other organic acid (for example tartaric acid) and cyclodextrin (for example alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin).Available exemplary fatty acid comprises caproic acid, enanthic acid, capric acid, lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, myristoleic acid, palmitoleic acid, hexadecenoic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexenoic acid.Available exemplary carboxylic acids salt comprises: Capric acid sodium salt or potassium, caprylate, laruate, myristate, palmitate, stearate, larane hydrochlorate, myristicol hydrochlorate, Petiolus Trachycarpi oil hydrochlorate, hexadecene hydrochlorate, oleate, linoleate, alpha-linolenic acid salt, arachidonate, eicosapentaenoic hydrochlorate, eruciate, docosahexenoic acid salt.Concrete carboxylate comprises Capric acid sodium salt, sodium caprylate and sodium laurate.Available concrete fatty amine comprises lauryl amine (N-dodecyl amine), decyl amine, nonyl amine, octylame, heptyl amice or hexylamine.Available exemplary sulfonic acid comprises perfluoroetane sulfonic acid, decane sulfonic acid (for example 1-decane sodium sulfonate), dodecane sulfonic acid, n-tetradecane sulfonic acid, hexadecane sulfonic acid, octadecane sulfonic acid, eicosane sulfonic acid, docosane sulfonic acid or lignocerane sulfonic acid.The concrete sulfonic acid that can mention comprises dioctyl sulfuration sodium succinate.

Therefore, the present invention also is specifically related to comprise the compositions and at least a tight regulator that is connected of the SAMe of physiologically acceptable dosage.In preferred embodiments, with the SAMe co-formulated of said tight connection regulator and physiologically acceptable dosage.

Closely the connection regulator can be effective in especially and improve slow release formulation, the section of the end in the more GI of targeting road.Close-connected porosity section (for example ileum and colon) endways is tighter, than for example duodenum (it is more porous than those of the GI section under more to be duodenal tight connection).In addition, the GI road under comparing more in the transhipment time in the GI road on top is faster.Still less the tight connection in hole shows that together with the combination of transporting the time in the more slow-speed of lower section the use in lower GI road early of tight connection regulator possibly be more effective on relative basis.Can expect that this effect prolongs SAME sending and under the situation of suppository formulation, be delivered to rectum in colon.

Consider close-connected existence in the mouth, comprise the formulation of the present invention that one or more closely connect regulator through use, it is practical that the oral delivery of the improvement of SAMe also is considered to.Therefore, non-parenteral formulation of the present invention be intended to comprise the oral cavity, comprise colon and rectum the zone of upper and lower intestinal as those of target.

Might use the regulator-enhanced component of the directed GI lower part of uniting, thereby produce the slow release formulation that enhanced absorption is arranged at the time durations that prolongs with top or regulator-enhancement component of the conventional orientation of GI-.

Therefore, the present invention relates to the SAMe and at least a tight compositions that is used for oral delivery that is connected regulator that comprises physiologically acceptable dosage particularly.

In some embodiments, compositions is used as buccal dosage forms.In other embodiment, compositions is used as suppository.

Preferably, the fitness that comprises special " absorption enhancer " of " closely connecting regulator " is confirmed through using SAMe Premeabilisation of cells Journal of Sex Research in vivo.Major part relevant cell system can satisfy experiment in these bodies, includes but not limited to Caco-2 cell (of embodiment 3).In addition, the use of list of references can provide the understanding to " absorption enhancer " or " closely connecting regulator " that uses among potential suitable the present invention in this area.

Increase the nano-carrier of sending of SAMe

The SAMe capsule sealed to cause sending in the carrier of using to the non-parenteral that is applicable to SAMe of nano-scale (for example nanoparticle and colloidal dispersion) to the increase of cell.Describe several and as if increased the approach that the intestinal absorption of commentaries on classics cell need not to damage epithelial tissue.Can these approach be classified as method, the increase medicine dissolution of stablizing medicine or the method that changes its characteristic, change Premeabilisation of cells thereby improve.Be suitable for promoting that the various colloidal dispersions of the absorption of SAMe are example with submicronized emulsion, polymer/nanometer particle, microgranule etc.The gastrointestinal picked-up of various these systems of physical chemical factor domination is arranged, comprise in order to strengthen the adjustable size of SAMe cellular uptake, distribution of sizes, denseness, hydrophobicity and surface nature.

The formulation administration of use shows SAMe enhanced-absorption and bioavailability

In some embodiments, of the present invention enhanced-absorb that the SAMe formulation relates to enhanced nutritional support or dietary supplement is healthy improves, include but not limited to that emotion improves articulation health and liver function.In the certain exemplary embodiment, the other supplement (it can not arrive through food (for example " dietetic food ")) that illness relates to through SAMe carry out the dietary management of disease.

Certain exemplary embodiment of the present invention relates to the method that in the experimenter, treats and/or prevents disease or illness, and said disease or illness are selected from but are not limited to following: psychology or mental sickness (for example psychotic/emotion or non--psychotic psychological illness for example are respectively depression and material related disorders); Nervous system disease/illness (for example central nervous system disease, for example Alzheimer), other sacred disease/illness (for example headache and sleep disorder); The disease relevant with central nervous system injury, hepatic disease/illness (for example alcoholic liver disease), cancer (for example entity and haematogenous cancer); Joint disease/illness (for example arthritis); Inflammatory diseases/illness (for example ulcerative colitis), autoimmune disease/illness (for example systemic lupus erythematosus (sle) and rheumatic arthritis), degenerative disease/illness (for example amyotrophic lateral sclerosis); Soft-tissue disease/illness (for example fibromyalgia illness); Pain disease/illness is relevant to height-or low-methylated hereditary illness, gastroenteropathy/illness; Cardiovascular disease/illness; By oxidation or the inductive illness of radical damage, this method comprises to said experimenter uses exemplary composition of the present invention with all or part of, and it promotes absorption and the bioavailability of the exogenous SAMe of physiology effective dose.

Embodiments more of the present invention relate to the therapeutic use of the disclosed exemplary composition of this paper in treatment psychology or mental sickness; Said psychology or mental sickness are selected from: anxiety neurosis, depression, drinking and eating irregularly; Two phasic property mental disorders; The abuse illness, dependency illness, Axis II illness and psychosis.In the certain exemplary embodiment, psychology or mental sickness are anxiety neurosis, are selected from: generalized anxiety disorder, posttraumatic stress disorder, social anxiety disease, panic disorder, schizophrenia and obsessive-compulsive disorder.In the certain exemplary embodiment, psychology or mental sickness are that depression is selected from: severe depression, multiple infarction dementia; Mild depression; Puerperal or depression in old age (etc.), parkinson depression, the HIV-depression of being correlated with; The of short duration depressive disorder of recurrent, dysthymia or depression NOS (not specifying in addition).In the certain exemplary embodiment, psychology or mental sickness are drinking and eating irregularly, are selected from: hungry disease, nervous anorexia, revelry drinking and eating irregularly, obesity or drinking and eating irregularly NOS.In the certain exemplary embodiment, psychology or mental sickness are two phasic property mental disorders, and abuse illness or dependency illness comprise abuse or depend on ethanol, nicotine, cocaine, codeine, oxycodone, hydrocodone or other anesthetis.In the certain exemplary embodiment, psychology or mental sickness are Axis II illness, are selected from the marginality abalienation.

In the certain exemplary embodiment; Illness is a nervous system disease, comprises for example parkinson of central nervous system (CNS) illness, Alzheimer; Angelman Syndrome (hereditary illness), Multiple Sclerosis (MS) and dull-witted preceding and/or cognitive impairment.

In the certain exemplary embodiment, illness is the coexistence illness, the coexistence depression that produces in the experimenter who carries out the treatment of one or more diseases or illness for example, and said disease or illness be such as but not limited to cancer, parkinson and HIV.In certain embodiments, the coexistence illness is caused by one or more therapies that are used to treat said one or more diseases or illness.

In the certain exemplary embodiment, illness is derived from the CNS damage, and for example spinal cord injury or brain injury evil is lost memory cognitive impairment and/or learning disorder.

In the certain exemplary embodiment, illness is a hepatic disease, is selected from alcoholic liver disease, fatty liver disease (non-alcoholic) hepatitis (virus and non-viral), hepatocarcinoma, oxidisability hepatic disease, HISS-dependency insulin patience, cholestasis and liver cirrhosis.

In the certain exemplary embodiment, illness is a cancer, is selected from the cancer that produces in following one or more: liver, colon, rectum; Ovary, urethra, testis, bladder, mammary gland; Stomach, esophagus, pancreas, incidence, lung; Blood, skin (for example actinic keratosis, basal cell carcinoma, shallow table basal cell carcinoma, squamous cell carcinoma and melanoma) and adenocarcinoma.

In the certain exemplary embodiment, illness is a joint disorders, for example arthritis and gonarthritis.

In the certain exemplary embodiment; Illness is an inflammatory diseases, is selected from: systemic lupus erythematosus (sle), Reye ' s syndrome, rheumatic fever, allergic rhinitis, myasthenia gravis, temporal arteritis, vasculitis, psoriasis, allergic dermatitis, acne erythematosa, eczema, alopecia universalis, scleroderma, pemphigus, contact dermatitis, ankylosing spondylitis, dermatomyositis, polymyositis, sprue, Guillain-Barre syndrome, multiple infarction dementia, back cerebrovascular accident reperfusion injury, Addison ' sShi disease, Hashimoto ' sShi thyroiditis, asthma, top respiratory inflammation symptom, chronic bronchitis, atherosclerosis, pernicious anemia, autoimmune hepatitis, prostatitis, pelvic inflammatory disease inflammatory diseases, Goodpasture ' s syndrome, Wegener ' s granuloma, chronic nephritis, Sjogrens syndrome or anaphylaxis conjunctivitis.

In the certain exemplary embodiment, illness is a disorder of gastrointestinal tract, for example inflammatory bowel (IBD), Crohn ' s disease or ulcerative colitis (UC).

In the certain exemplary embodiment, illness is a for example fibromyalgia of soft tissue diseases.

In the certain exemplary embodiment, illness is the pain illness, for example fibromyalgia, chronic headache, herpes zoster, reflex sympathetic dystrophy and polyneuropathy.

In the certain exemplary embodiment, illness is a cardiovascular disease, and it is relevant to height-or low-homocysteine mass formed by blood stasis, for example coronary heart disease, apoplexy, peripheral vascular disease and Atheromatosis.

In the certain exemplary embodiment, illness is relevant to heredity or medical conditions, and it relates to the defective of the approach of methylating, for example methylenetetrahydrofolate reductase deficiency.

In the certain exemplary embodiment, the cause of disease of illness can comprise oxidation or radical damage, is selected from chronic fatigue syndrome, temporal arteritis, vasculitis, multiple infarction dementia, chronic emphysema or chronic nephritis.

Of the present invention enhanced-absorb in the advantage that the SAMe formulation provides; Comprise owing to the facility that reduces every day administration brings with follow experimenter's compliance of improvement, the side effect performance of improvement (for example reduce gastric irritation be reduced in manic depressed experimenter potentially or be among the experimenter of manic episode cause manic trend) and realize other side effect that the SAMe (typically about 400 to about 3200mg SAME ion/sky, more typically about 800 to about 1600mgSAME ion/sky) of the needed relative high dose of desired effects is correlated with or causes.

Use like this paper, term " desired effects " comprises " therapeutic effect ", " pharmacy effect ", " diet effect " (for example as dietetic food), " nutraceutical effect " and " nutritive validity ".Therefore; " desired effects " is included at least a symptom that alleviates physiology illness or morbid state among the experimenter, improves at least a performance variable (concentration, memory, emotion, nutritional status or the liver state that for example improve) when perhaps in the experimenter, being used as supplementary." desired effects " can the application of the invention SAMe formulation clinical, pharmacy or veterinary's dosage regimen of nutritional supplementation effect or the application of the invention SAMe formulation use and realize.

Be used for according to the method for the invention suitable experimenter with the compositions administration comprise warm animal for example the people, raise and train or external animal or domestic animal; The birds experimenter who raises and train is chicken and duck for example; And the laboratory animal that is applicable to the research purposes.When being used in experimenter's treatment disease or illness, it is medicable in the context of the present invention that the multiple symptom of specific physiology illness and morbid state is considered to, and its details is set forth as follows.Yet, it should be understood that various disease states understood by one of ordinary skill in the art is not static, and it is identical for the performance variable that is relevant to nutritional supplementation.Therefore, although top description be intended to illustrate can use according to of the present invention enhanced-absorb various illness, morbid state, symptom or the performance variable of the treatment of SAMe formulation, those skilled in the art will estimate this type of application knowledge.

Use the administration of multiple dose unit

Certain exemplary embodiment of the present invention relates to and in the experimenter, treats and/or prevents one or more diseases; Wherein treat and/or prevent one or more diseases and/or illness and comprise using and absorb enhanced formulation that this formulation comprises S-adenyl residue methionine (SAMe) or its proprietary salt of physiologically acceptable dosage to said experimenter.

Other exemplary more of the present invention relate to SAMe supplementary and/or the dietary supplement that in the experimenter, improves one or more nutritional properties variablees; Wherein the nutritional properties variable is one or more in concentration, memory, emotion, the nutritional status regulating liver-QI state, and the enhanced formulation of absorption that wherein is applied to the experimenter comprises S-adenyl residue methionine (SAMe) or its other proprietary SAMe salt of physiologically acceptable dosage.

In the certain exemplary embodiment, absorb enhanced SAMe and can be divided into many every days of dosage.Many every days dosage to need not be identical, and can comprise one or more dosage forms of associating.In the certain exemplary embodiment, enhanced-as to absorb SAMe and can be divided into two or more of dosage every day.Each dosage can be used as single dosage unit and uses, and for example single tablet, capsule or capsule sheet perhaps replacedly can be divided into multiple dose unit and use.In some embodiments, two doses every day (SAME ion/dosage of about 100 to about 1600mg) can be divided into a kind of to four kinds of dosage units of SAME ion/unit of about 100 to about 800mg.Under each situation, dosage unit form can or postpone to discharge dosage unit etc. for capsule, tablet, capsule sheet (list or multicell).In some embodiments, absorption enhancer and SAMe are arranged in the peroral dosage form, and wherein the independent compartment of peroral dosage form contains absorption enhancer or SAMe.In other embodiments, absorbing promotion property technology applies in the SAMe dosage form separately.Preferably, peroral dosage form is tablet, capsule or gel-capsule.

Conventional SAMe administration applies SAME ion/one day twice (BID) of maximum 1600mg usually, to realize the maximum activity of medicine.Tablet is commercially available with 200mg and 400mg dosage SAME ion the most usually, and this requires the experimenter to absorb the 4-8 sheet every day.With respect to potential mistake (if promptly forgetting administration) in the time quantum of needs and the successive administration, this is inconvenient.The present invention has the new compositions and the method for evaluation, and it reduces the effective dose (promptly than conventional dosage regimen, the tablet quantity that reducing every day needs realizes identical or better effect) of SAMe, and/or elimination needs twice administration in a day.Absorb through improving SAMe, can get the method that a kind of new SAMe treats, it reduces and induces the needed SAMe dosage of effective response through the compositions that comprises one or more absorption-promotion property technology is provided.These exemplary " low dosage " formulations can provide lower every day the ball number, this is of value to takes SAMe person because this will reduce the time, cost and the not convenient property of clothes heavy dose certainly.

The certain exemplary embodiment relates to using once a day and is selected from physiologically acceptable dosage.In some embodiments, dosage can be used in single dosage unit once a day, for example single tablet, capsule or capsule sheet.In other exemplary, single dose can be used as in time place's mode of taking a plurality of tablets, capsule or capsule sheet and uses.In some embodiments; For example; Every day, the dosage of about SAMe of 400 to 3200mg can be divided into two, three, four or more multi-disc agent, capsule or capsule sheet, and it is about 50 to 2000, preferred about 100 SAMe units to 1600mg, in some preferred embodiments; Every day, dosage can comprise two, three or four units (for example tablet, capsule or capsule sheet), and it is SAME ion/unit of about 100 to 800mg.The proper dosage scheme comprises: four units, the SAME ion of each about 50-400mg of unit, for example the SAME ion of each unit 50,100,150,200,250,300,350 or 400mg; Three units, the SAME ion of each about 50-1000mg of unit, each unit 50,100,150,200,250,300,350,400,450,500,550,600,650,700,750,800,850,900,950 or 1 for example, the SAME ion of 000mg; Two units, the SAME ion of each about 50-1600mg of unit, for example each unit about 50,100,150,200,250,300,350; 400,450,500,550,600,650,700,750; 800,850,900,950,1000,1050,1100,1150; 1200,1250,1300,1350,1400,1450,1500,1550 or the SAMe ion of 1600mg.

Certain exemplary embodiment of the present invention relates to " low dosage " SAMe compositions.Through improving the bioavailability of exogenous SAMe, application dosage every day of SAMe can have the compositions that the SAMe of improvement absorbs and reduces basically through use.These exemplary " low dosages " treatment can realize lower ball number every day.

Feed vs. fasting dosage

In some embodiments of the present invention, can guarantee advantageously that the experimenter takes food or fasting (for example whole night, at least about 6 hours, particularly about 8 hours).According to thinking; Use to the experimenter the present invention absorb enhanced SAMe formulation in, at once before (promptly less than about 30; Especially less than about 15 minutes) or (for example less than about 10 minutes) feed at once afterwards can improve or reduce the speed of gastric emptying, therefore the speed of SAMe is absorbed in influence from formulation.Therefore, in some embodiments, the present invention is contained with food and is used the enhanced SAMe formulation of absorption of the present invention together, and wherein food is before the SAMe treatment or absorb in the process.

Associating with other active component

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component, and said active component is the routine prescription medicine or is used for treating and/or preventing disease or illness the experimenter that said disease or illness are selected from but are not limited to following: psychology or mental sickness are (for example psychotic or non--psychotic psychological illness; For example be respectively depression and material related disorders); Nervous system disease/illness (for example central nervous system disease for example Alzheimer), other sacred disease/illness (for example headache and sleep disorder), the disease relevant with central nervous system injury; Hepatic disease/illness (for example alcoholic liver disease); Cancer (for example entity and haematogenous cancer), joint disease/illness (for example arthritis), inflammatory diseases/illness (for example ulcerative colitis); Autoimmune disease/illness (for example systemic lupus erythematosus (sle) and rheumatic arthritis); Degenerative disease/illness (for example amyotrophic lateral sclerosis), soft-tissue disease/illness (for example fibromyalgia illness), pain disease/illness; Be relevant to height-or low-methylated hereditary illness; Gastroenteropathy/illness, cardiovascular disease/illness and all or part of by oxidation or the inductive illness of radical damage; Comprise to said experimenter and use exemplary composition of the present invention that it promotes absorption and the bioavailability of the exogenous SAMe of physiology effective dose.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing psychology or mental sickness the experimenter, includes but not limited to for example saredutant, Corticotropin releasing factor antagonists mifepristone, atypical antipsychotic agent for example lithium or three reuptake inhibitors of Aripiprazole, the conventional antidepressant reinforcing agent that uses for example for example of tricyclics (TCA), Fourth Ring class antidepressants, aminoketones, phenylpiperazine class, selective serotonin reuptake inhibitor (SSRI), oxidase inhibitor (MAOI), serotonin-NRI (SNRI), norepinephrine-serotonin reuptake inhibitor (NSRI), dopamine reuptake inhibitor, norepinephrine-dopamine reuptake inhibitor, NRI, selective serotonin reuptake reinforcing agent, norepinephrine and 5-hydroxy tryptamine specific anti down, Substance P receptor antagonist, neurokinin receptor antagonists.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more device therapies; Said device therapy is the routine prescription medicine or is used for treating and/or preventing psychology or mental sickness the experimenter, includes but not limited to ECT (electric convulsive therapy) and electric shock therapy.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing nervous system disease/illness the experimenter, includes but not limited to for example for example for example donepezil, neuroprotective, nootropics, central nervous system's regulator, anti-amyloidosis agent of memantine, cholinesterase inhibitor of lyrica, alpha-amido-3-hydroxy-5-methyl base-4-isoxazole propanoic acid (AMPA) receptor antagonist, methyl phosphonate (NMPA) receptor antagonist, histamine receptor antagonists, nitric oxide (NO) regulator, glutamate receptor antagonists, acetylcholinesteraseinhibitors inhibitors, dopamine agonist, N-methyl-D-aspartate (NMDA) receptor antagonist of convulsion.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing hepatic disease the experimenter; Include but not limited to for example IFN-of antiviral drugs, ribavirin, lamivudine; Steroid, antibiotic and zinc acetate.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component, and said active component is the routine prescription medicine or is used for treating and/or preventing cancer the experimenter, includes but not limited to chemotherapeutics, drug resistance regulator; Monoclonal antibody; Cytokine (for example interferon and interleukin), immune cell factor, somatomedin; Chemical protective agent, vaccine and other biological answer-reply regulator.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing joint or inflammatory diseases/illness the experimenter, includes but not limited to analgesic, nonsteroidal anti inflammatory chemical compound (NSAID), disease alleviation property antirheumatic (DMARD), corticosteroid, anakinra (interleukin-1 receptor antagonist), COX-2 inhibition, GABA-B (GABAB) receptor stimulating agent for example baclofen, latent medicine for example Benzodiazepines, tumor necrosis factor (TNF)-inhibition medicine and the adjusting immunoreactive other drug (immunosuppressive drug) of imitating of GABAA receptor.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing autoimmune disease/illness the experimenter, includes but not limited to that DMARD, corticosteroid, anakinra (interleukin-1 receptor antagonist), TNF-suppress medicine and regulate immunoreactive other drug (immunosuppressive drug).

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing degenerative disease/illness the experimenter, includes but not limited to NSAID, COX-2 inhibition, GABAB receptor stimulating agent for example baclofen and the latent for example Benzodiazepines of medicine of imitating of GABAA receptor.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing soft tissue diseases/illness the experimenter, includes but not limited to milnacipram, lyrica, SNRI, NSRI, loosening all muscles agent, tranquilizer, analgesic and NSAID.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing the experimenter and is relevant to height-or low-methylated genetic diseases/illness, include but not limited to methionine, MTA (5 '-deoxidation-5 '-(methyl mercapto) adenosine) and other SAMe metabolite.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing gastroenteropathy/illness the experimenter, includes but not limited to for example azathioprine (Immuran), Ismipur (6-MP), methotrexate and ciclosporin (Sandimmune), the conventional antibiotic that uses metronidazole (Flagyl) and ciprofloxacin (Cipro) and biological agent infliximab (Remicade) for example for example of 5-aminosalicylic acid (5-ASA) medicine, corticosteroids (prednisone), immunoregulation medicament.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing cardiovascular disease/illness the experimenter, includes but not limited to statins, Angiotensin-Converting (ACE) inhibitor, ASA, SAMe cleavage product for example methionine, MTA and folic acid, cardioprotectant, blood vessel protective agent, blood coagulation inhibitor.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing the experimenter all or part of by oxidation or the inductive illness of radical damage, includes but not limited to antioxidant for example vitamin A, vitamin C, vitamin E, polyphenol, flavonoid, selenium, carotenoid.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and one or more active component; Said active component is the routine prescription medicine or is used for treating and/or preventing the experimenter all or part of by the inductive illness of central nervous system injury (for example brain injury or bone marrow damage), includes but not limited to neuroprotective, nootropics, CNS regulator, analgesic, muscle relaxant, apoptosis inhibitor, bone regulator, antioxidant.

Certain exemplary embodiment of the present invention relates to the associating of SAMe and methionine, MTA, folic acid, vitamin B6 and/or B12, because they are relevant to the generation that reduces homocysteine separately.Therefore; According to thinking; The associating of SAMe and methionine, MTA, folic acid, vitamin B6 and/or B 12 can cause the replenishing of increase of SAMe through following manner: the ability of the natural generation SAMe of enhancing body, and use the exogenous SAMe of the bioavailability that shows enhanced absorption and improvement to replenish SAMe simultaneously.The term " folic acid " that uses like this paper is meant all natural and vitamin Bs 9 synthesized form, includes but not limited to folic acid, tetrahydrofolic acid and L-methopterin.

In some embodiments, according to of the present invention exemplary enhanced-absorb the SAMe dosage form can be included in the have independent dosage form test kit of (containing at least a other active component), said active component for example is one or more such chemical compounds; This chemical compound is suitable is the routine prescription medicine or is used for treating and/or preventing disease or illness the experimenter, and said disease or illness are selected from but are not limited to following: psychology or mental sickness (for example psychotic/emotion or non--psychotic psychological illness for example are respectively depression and material related disorders); Nervous system disease/illness (for example central nervous system disease for example Alzheimer), other sacred disease/illness (for example headache and sleep disorder), the disease relevant with central nervous system injury; Hepatic disease/illness (for example alcoholic liver disease); Cancer (for example entity and haematogenous cancer), joint disease/illness (for example arthritis), inflammatory diseases/illness (for example ulcerative colitis); Autoimmune disease/illness (for example systemic lupus erythematosus (sle) and rheumatic arthritis); Degenerative disease/illness (for example amyotrophic lateral sclerosis), soft-tissue disease/illness (for example fibromyalgia illness), pain disease/illness; Be relevant to height-or low-methylated hereditary illness; Gastroenteropathy/illness, cardiovascular disease/illness and all or part of by oxidation or the inductive illness of radical damage; Comprise to said experimenter and use exemplary composition of the present invention, it improves the absorption of the exogenous SAMe of physiology effective dose.

Except one or more other compositions or methionine, MTA, folic acid, vitamin B6 and/or the B 12 that gives an example above the SAMe associating, of the present invention exemplary enhanced-inhale using of SAMe formulation and also can strengthen the other drug that the experimenter takes or the effect of supplementary.Therefore, certain exemplary embodiment of the present invention relates to the associating of SAMe and medicine or nutrient compounds, and said medicine or nutrient compounds have used and be used to treat other diseases to improve the activity of said medicine or nutrient compounds.

The present invention also further describes through the following example.Although use some specificity aspect of the present invention, these embodiment should not be considered to restriction or limitation discloses scope of the present invention.

Embodiment

Embodiment 1

The SAMe coated composition that changes causes GI section-specific SAMe to absorb

In order better to understand the intravital absorption characteristic of SAMe, at first produce standard, not by coating comprise the SAMe tablet, and use then one in three zoness of different in GI road as target phase-specific coating coating.

Use standard procedure well known by persons skilled in the art preparation comprise microcrystalline Cellulose, croscarmellose, silica sol and magnesium stearate not by the SAMe tablet of coating.In order to improve the compressibility of compositions, use dry compression method to make the SAMe powder become graininess.Each excipient inside-granule and outside-granule between the stage separately.Use is equipped with elongated the Ellipse tool a position and the rotary tablet machine that remaining position is inaccessible compresses final press sheet mixture.Relative ambient humidity is remained on about 30% or lower, and in whole process with ambient temperature be controlled at 20 and 30C between.The granule that in this formulation, uses has good mobile performance and confirms does not adhere in compression or selects.

For the SAMe of (duodenum & jejunum) discharges as target in the GI road that closes on, that routine is used, known more than about 5.5 pH dissolved Eudragit

coating be applied to the SAMe tablet (EUDRAGIT be Rohm GmbH; Darmstadt, the registered trade mark of Germany).In order before using pH-dependency coating, to improve the surface nature of these tablets, at first use commercially available seal-coat.

Use comprises second formulation of the second commercially available Eudragit

coating to send SAMe to terminal GI road (ileum/ascending colon), because it is dissolved among about pH more than 7.0.As above, at first with commercially available this formulation of seal-coat preparation.

Finally, through Research on Contract tissue (Contract Research Organization) the rate controlled coating is applied to not by on the SAMe label tablet of coating, this rate controlled coating is used to provide the SAMe in whole GI of running through of metering road to discharge.

As scheme shown in the IA, obtain sending of SAMe in all three zones in GI road, and each position result is in the pharmacokinetic profiles figure of the uniqueness that different Cmax and Tmax value are arranged (figure IB).Under the situation of the coating tablet of pH 5.5 and pH 7.0, the expected time of undressing is that the pH sensitivity of coating is together with expectation transhipment or the function of the time of advent for target phase.The Tmax that observes is corresponding with the time of expection experimentally.Under the situation of speed-control coating that is the non-solubility coating, do not seal coating, maximum medicine is sent corresponding in Tmax and the colon.

Therefore, judge, confirms that three kinds of formulations, three diverse locations in the GI road show and the sending of near-end, terminal and the corresponding to target of GI section extension like Tmax through them.The core of three kinds of products is identical with application dose, but as being different significantly through Cmax with the dosage delivered shown in the AUC.Relative bioavailability is associated with the tight hole that is connected of target phase.

Embodiment 2

The body inner analysis of absorption enhancer

Absorption enhancer as the absorption of the new formulation that increases SAMe and thus bioavailability use through or with one or more absorption enhancer co-formulated SAMe or use SAMe jointly with one or more absorption enhancers and realize.Use jointly that be not must be in the identical time because with said absorption enhancer in the using or using in front or rear rational time of the said proprietary preparation of SAMe, this may be more effective.

The evaluation that can find suitable absorption enhancer in this area maybe this evaluation can be accomplished in vivo.After being applied to animal model, can measure the activity in vivo of the compositions that comprises SAMe and one or more absorption enhancers.Preferably; Animal model comprises pharmacokinetics (PK) model, wherein uses the pharmacology to go up effective administration and uses candidate formulation to non-rodent (for example Canis familiaris L., pig, miniature pig or primate) and pipette blood, urine, cerebrospinal fluid (CSF) or other appropriate biofluid in the period in periodicity.In order to make the scattergram of concentration vs. time, biofluid is used to test reactive compound.In order to assess the body giving drugs into nose, analyze these data and calculate pharmacokinetic parameter for kinetic activity.The modal pharmacokinetic parameter of in these models, analyzing is C _Max, T _Max, and TG-AUC (AUC).

Selectively, or except the PK model, people can effective utilization identify suitable absorption enhancer as measuring, through using non-rodent model to be used for hepatic disease or osteoarthritis is example.

The mark of blood plasma and urine comprises measures the mark that is suitable for various diseases/illness.

The change of gene expression comprises the serial analysis of change (metabolism group) of change (proteomics) or the metaboilic level of gene expression (genomics) and protein expression.

Embodiment 3

Screening in the body of absorption enhancer

Except above-mentioned, the evaluation of suitable absorption enhancer also can be used simply, the interior screening of standard body is analyzed and realized.In the present invention, than untreated Caco-2 cell monolayer, SAMe is used to measure the medicament that increases the amount that SAMe absorbed by said Caco-2 cell through the permeability with the Caco-2 cell monolayer of absorption enhancer treatment.Caco-2 cell line derive from human colorectal cancer with and be widely used in the cells in vivo culture model (Stewart, B., (1995) Pharm.Res.12:693) of the research that gastrointestinal drug absorbs.In these models, pure cell line is grown on semipermeable membrane.Pharmaceutical formulation is positioned over the top side or the basic side of cell monolayer, and measures transhipment via measurement at the drug level of film opposite side.

In the Caco-2 of this use cell line is from American type culture collection (ATCC).The Caco-2 cell be grown in the improved Eagle ' of Dulbecco ' s s culture medium (DMEM, Gibco) in, replenish 20%FBS (hyclone, Gibco), (NEAA is Gibco) with 2mM L-glutaminate (Gibco) for the nonessential aminoacid of 100uM.Use Beckton Dickinson BIOCOAT

HTS Caco-2 Assay System test kit obtains 6.6x10 ⁵Cell/cm ²Inoculum density (BIOCOAT is Collaborative Biomedical Products, Inc., Bedford, Massachusetts, the registered trade mark of USA).The cell that in transhipment research, uses was grown before experiment 3 days.Condition of culture be under 37 ℃, 5%CO ₂Atmosphere in 100% humidity under.

For the permeability that passes the Caco-2 cell monolayer, the transhipment medium of use is to contain the Hank ' s buffer salt solution (HBSS that D-glucose and pH are adjusted to 7.4 HEPES; Buy from Gibco).According to the program of manufacturer for the Caco-2 test kit, or with SAMe toluenesulfonic acid two sulphuric acid or SAMe 1, the 2mM aqueous solution of 4-fourth disulfonate adds top side or basic side.Behind 120 minutes incubation, pass through LC/MS (LC/MS) working sample.Use the integrity of Lucifer Yellow Assay monitoring monolayer.For example, than the absorption of SAMe self, absorption enhancer (and being specially tight connection opening agent), EDTA (in the 2mM hole) and the medium that do not have calcium are for the infiltrative effect of the Caco-2 of SAMe.Propranolol is the high osmosis mark, and it is used as the positive control for the molecule that is easy to absorb.

Following table 2 results and be low for two kinds of salt in those absorptions that show SAMe self shown in Fig. 2 are as through low apparent infiltration coefficient (Papp=0.41x10 ^-6And 0.50x10 ^-6Cms ^-1Be respectively the p-methyl benzenesulfonic acid dithionate of the SAMe of top to bottom and bottom to top-direction; And Papp=0.50x10 ^-6And 0.60x10 ^-6Cm s ^-1Be respectively top to bottom and bottom to top-direction SAMe 1,4-fourth disulfonate) prove.Interesting is, two kinds of stable salt of SAMe, and p-methyl benzenesulfonic acid dithionate and 1,4-fourth disulfonate has identical permeability scattergram in the experimental error scope, and this provides the proof of their bioequivalence.Carry out remaining penetration study with SAMe p-methyl benzenesulfonic acid dithionate.

The osmotic value of the mensuration of SAMe salt is far below using the high osmosis mark, and Propranolol (is respectively 22.4x10 ^-6And 18.4x10 ^-6Cm s ^-1) osmotic value measured.Be independent of and/or be similar to from the top characteristic that is considered to the bypass transhipment to base portion and from the infiltration coefficient of the concentration of base portion to bottom direction.Support the bypass transporting mechanism (like table 2 and shown in Figure 2) of SAMe through the infiltrative increase of 13-24 multiple SAMe in the buffer at no calcium and when the increase of the 1.3-5.0 multiple in the presence of known tight connection opening agent, EDTA at this.

Table 2: the permeability of SAMe that passes the monolayer of Caco-2 cell

Embodiment 3a

Closely connecting increase SAMe permeability in the presence of the regulator

Be organized in by Research on Contract and carry out additional C aco-2 test in a large amount of tight connection opening agent.Be similar to the above; From ATCC, obtain Caco-2 cell line; And growth in DMEM (Sigma-Aldrich), replenish 20%FBS (Sigma-Aldrich), the nonessential aminoacid of 100uM (Sigma-Aldrich) and 2mM L-glutaminate (Sigma-Aldrich).The Caco-2 cell of growth in Tissue Culture Flask trypsinized, be suspended in the medium, and suspension is applied in the hole of BioCoat Cell Environment of collagen protein-coating for 24-hole gauge lattice, 24,500 cells in every hole.Make this cell in three weeks, grow and differentiation every 2-days cycle feedings.

For from the top to the permeability of base portion, the 2mM aqueous solution of SAMe toluenesulfonic acid dithionate is added to the top side, and measures infiltration capacity in basic side.Top side and basic side buffer contain the improvement transport buffer (25mM HEPES, IxHank ' s Balanced Salt Solution (Sigm-Aldrich)) of pH 7.4..With these buffer incubations Caco-2 cell 2 hours, and the buffer agent that pipettes receiver-side was analyzed through LC/MS/MS.In order to increase the stability of SAMe, after analysis immediately with receptor, donor with to the 0.2N HCl dilution of drug solns with equal volume.With donor and administration solution dilution 100-multiple, thereby guarantee that this concentration is in the range of linearity of analyzing.

In order to confirm the integrity of Caco-2 cell monolayer,, experiment carries out the measurement of TEER (transepithelial electrical resistance) when finishing in every hole.

Use the permeability (Papp) of computes SAMe:

$\mathrm{Papp}=\frac{\frac{\mathrm{dQ}}{\mathrm{dt}}}{\mathrm{CoA}}$

Wherein dQ/dt is a permeability, C ₀Be the initial concentration of reagent, and A is the area of monolayer.

As shown in table 3 below, the existence of two kinds of different fatty acids (or C10 fatty acid or sulfonic acid) causes the infiltrative significant increase of SAMe.

Each tests zwitterionic surfactant (3-sulfopropyl hexadecyldimethyl benzyl ammonium ammonium and chlorination Petiolus Trachycarpi carnitine) for their effect of SAMe picked-up, and the both shows the infiltrative significant increase of SAMe as shown in table 3.In addition, alpha-cyclodextrin and dicarboxylic acids respectively cause the infiltrative 5-6 of SAMe increase doubly.Low and high permeability contrast, ranitidine and warfarin are checked the use of these absorption enhancers as screening technique in the body respectively, and said screening technique is used to measure these medicaments for the infiltrative effect of the SAMe that passes the Caco-2 monolayer.And, with independent SAMe, than in the presence of calcium or closely connect regulator, chlorination Petiolus Trachycarpi carnitine or caprate in the presence of the permeability of SAMe be illustrated in the chart of Fig. 3.

Table 3: the permeability of SAMe in the presence of various tight connection regulators

Embodiment 4

Blood plasma level with respect to the blood plasma level SAMe metabolite of SAMe does not increase

If SAMe is by the liver active metabolism in using, think that the blood plasma level of one or more SAMe metabolite can increase significantly after using, this is rational.Should theory in order to test, this researcher is determined at the level of S-adenosyl homocysteine (SAH) under each time point behind the commercially available SAMe formulation of using 1600mg dosage, the main metabolism of SAMe.

As shown in Figure 4, at all time points of measuring, the PC of SAH (it is under the ratio that is lower than ten times of SAMe concentration, to draw) is the concentration that is markedly inferior to SAMe self.Also measure other SAMe metabolite and, be similar to SAH, do not have difference (result does not show) at their baseline values.

These results confirm that the SAMe metabolism is not the main cause of the low bioavailability of SAMe in using.

Embodiment 5

Can effectively the SAMe that is delivered to stomach be absorbed into blood plasma

For fear of the low-pH environment that by the people is the harshness that causes degrading, those skilled in the art think that SAMe sends and must walk around stomach.In order better to understand the mechanism that SAMe absorbs, and in order to control its bioavailability, that assesses SAMe thus is released into gastric environment and its absorption.

Use like embodiment 1 described standardization program, with not being formulated in the tablet that comprises microcrystalline Cellulose, croscarmellose, silica sol and magnesium stearate by the SAMe of coating.

In this formulation, there is not enteric coating to be intended to cause the release of SAMe at gastric.Use the existence of back at each time point blood plasma Chinese medicine, the pharmacokinetic profiles figure that institute gets through mensuration.With the 400mg SAMe of single dose give seven health with on an empty stomach, in the male volunteers.

As shown in Figure 5, seven use 400mg dosage not by the experimenter's of the SAMe formulation of coating average C _MaxBe about 145ng/mL.These results show: with report opposite repeatedly in this area, need do not use the formulation of enteric coating can SAMe be delivered in the stomach, and produce the significant suction shown in the plasma sa Me level of reporting at this.

Claims (30)

1. non-parenteral compositions comprises the S-adenosylmethionine that promotes at least a physiology effective dose of property technical tie-up with at least a absorption.

2. compositions according to claim 1, wherein said absorption promote the property technology to be gastric retention administration adjuvant, gastrointestinal section-specific delivery system, chemically derived absorption enhancer, closely to connect a kind of in penetrating agent, closely connection opening agent, nano-carrier, diet program and the dosage regimen.

3. according to described compositions among the claim 1-2, wherein said non-parenteral compositions is a composition for oral administration.

4. according to described compositions among the claim 1-3, wherein said non-parenteral compositions is incorporated in dietary supplement or the dietetic food.

5. according to described non-parenteral compositions among the claim 1-4, comprise and the tight S-adenosylmethionine that is connected at least a described physiology effective dose of at least a associating in penetrating agent and the tight connection opening agent.

6. at least a in the non-parenteral compositions according to claim 4, wherein said tight connection penetrating agent and tight connection opening agent is selected from cleaning agent, surfactant, zwitterionic surfactant, unsaturated ring urea, fatty acid, fatty amine, alkylsulfonate, bile acid, organic acid, cyclodextrin, chelating agen, any salt noted earlier and combination thereof.

7. non-parenteral compositions according to claim 6, at least a zwitterionic surfactant that comprises in wherein said tight connection penetrating agent and the tight connection opening agent.

8. non-parenteral compositions according to claim 6, at least a fatty acid or its salt of comprising in wherein said tight connection penetrating agent and the tight connection opening agent.

9. non-parenteral compositions according to claim 6, at least a fatty amine or its salt of comprising in wherein said tight connection penetrating agent and the tight connection opening agent.

10. non-parenteral compositions according to claim 6, at least a bile acid or its salt of comprising in wherein said tight connection penetrating agent and the tight connection opening agent.

11. at least a in the non-parenteral compositions according to claim 6, wherein said tight connection penetrating agent and tight connection opening agent comprises cleaning agent, surfactant, unsaturated ring urea and organic acid, cyclodextrin, chelating agen, any their salt or its two kinds or more kinds of combinations.

12., wherein at least a portion of said compositions is configured to be dissolved at least a in stomach, duodenum, jejunum and the ileum according to described non-parenteral compositions among the claim 1-11.

13. according to described non-parenteral compositions among the claim 1-11, wherein at least a portion with said compositions is configured to be dissolved in large intestine or the colon.

14. according to claim 12 or 13 described non-parenteral compositionss, wherein said compositions is introduced pH sensitivity coating.

15. the method for the bioavailability of the exogenous SAMe that an increase is used to the experimenter; Said method comprises to described experimenter uses non-parenteral compositions, and said compositions comprises the S-adenosylmethionine that promotes at least a physiology effective dose of property technical tie-up with at least a absorption.

16. method according to claim 15, wherein said absorption promote the property technology be gastric retention make up a prescription adjuvant, gastrointestinal section-specific delivery system, chemically derived absorption enhancer, closely connect a kind of in penetrating agent, closely connection opening agent, nano-carrier, diet program and the dosage regimen.

17. according to claim 15 or 16 described methods, wherein said compositions is a composition for oral administration.

18. according to described method in the claim 15 to 17, wherein said compositions is incorporated in dietary supplement or the medicine food.

19. according to described method in the claim 15 to 17, wherein said compositions comprises and the S-adenosylmethionine that closely is connected the penetrating agent and the physiology effective dose of at least a associating of tight connection opening agent.

20. method according to claim 19; Wherein said compositions comprises at least a in tight connection penetrating agent and the tight connection opening agent, and at least a in said tight connection penetrating agent and the tight connection opening agent is selected from cleaning agent, surfactant, zwitterionic surfactant, unsaturated ring urea, fatty acid, fatty amine, alkylsulfonate, bile acid, organic acid, cyclodextrin, chelating agen, any foregoing salt and combination thereof.

21. method according to claim 20, wherein said compositions comprise at least a in tight connection penetrating agent and the tight connection opening agent, at least a zwitterionic surfactant that comprises in said tight connection penetrating agent and the tight connection opening agent.

22. method according to claim 20, wherein said compositions comprise tight connection penetrating agent and tight at least a in the connection opening agent, said tight connection penetrating agent and tight at least a fatty acid or its salt of comprising in the connection opening agent.

23. method according to claim 20, at least a fatty amine or its salt of comprising in wherein said tight connection penetrating agent and the tight connection opening agent.

24. method according to claim 20, at least a bile acid or its salt of comprising in wherein said tight connection penetrating agent and the tight connection opening agent.

25. at least a in the method according to claim 20, wherein said tight connection penetrating agent and tight connection opening agent comprises cleaning agent, surfactant, unsaturated ring urea and organic acid, cyclodextrin, chelating agen, any their salt or its two kinds or more kinds of combinations.

26., wherein at least a portion of said compositions is configured to be dissolved at least a in said stomach, duodenum, jejunum and the ileum according to described method among the claim 15-25.

27. according to described method among the claim 15-25, wherein at least a portion with said compositions is configured to be dissolved in said large intestine or the colon

28. according to described method in the claim 26 and 27, wherein said compositions is introduced pH sensitivity coating.

29., wherein before or after the using of the said compositions of the S-adenosylmethionine that comprises said at least a physiology effective dose, use said absorption and promote the property technology according to described method among the claim 15-28.

30. one kind in the patient treatment be selected from the method for following illness: psychology or mental disease (for example psychotic disease/emotion or OP sexual psychology illness; Be example with depression and material dependency illness respectively), nervous system disease/illness (central nervous system disease for example; With the Alzheimer is example), other sacred disease/illness (for example headache and sleep disorder), with to the relevant disease of central nervous system's damage, hepatic disease/illness (for example alcoholic liver disease), cancer (for example entity and haematogenous cancer), joint disease/illness (for example arthritis), inflammatory diseases/illness (for example ulcerative colitis), autoimmune disease/illness (systemic lupus erythematosus (sle) and rheumatic arthritis), degenerative disease/illness (for example amyotrophic lateral sclerosis), soft-tissue disease/illness (for example fibromyalgia illness), pain disease/illness, with height-or low-relevant hereditary illness that methylates, gastroenteropathy/illness, cardiovascular disease/disease favour, all or part of by oxidation or the inductive illness of radical damage, said method comprises the said compositions of any item in its patient of needs uses according to claim 1-14.

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